This invention relates to certain salts of sertraline, and to a sustained-release dosage form of sertraline having an improved side effect profile, and to a method of treating a psychiatric or other illness comprising administering sertraline in such a sustained-release dosage form to a mammal, including a human patient, in need of such treatment
Sertraline is a selective serotonin reuptake inhibitor (SSRI), which is useful, inter alia, as an antidepressant and anorectic agent, and in the treatment of obsessive-compulsive disorder, premenstrual dysphoric disorder, post-traumatic stress disorder, chemical dependencies, anxiety-related disorders, panic and premature ejaculation. See U.S. Pat. No. 4,536,518, Published International Application WO 92/18005, U.S. Pat. No. 5,130,338, U.S. Pat. No. 4,971,998, Published International Application WO 92/00103, U.S. Pat. No. 5,061,728, U.S. Pat. No. 4,940,731, and U.S. Pat. No. 4,962,128, each of which is incorporated herein by reference. Sertraline is also known as (1S-cis)-(4-(-3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine, has the empirical formula C12H17NCl2, and has the structural formula 
Sertraline is most commonly prescribed for therapy of depressive illness, in the general dose range 50-200 mg/day. Sertraline has an elimination half-life of 23 hr, and is dosed once daily.
Patients are generally initiated on sertraline at a dose of 50 mg/day. Patients who do not respond at the 50 mg dose are given higher doses. Initiation at doses greater than 50 mg is generally avoided, when possible, because side effects such as dizziness, tremor, and sweating, and gastrointestinal upset are generally believed to be more severe at higher doses. If necessary to achieve efficacy, higher doses may be reached by slow titration up from lower doses. Improved sertraline dosage forms which exhibited a lower incidence and/or severity of side effects would be advantageous because (1) patient comfort would be improved, and (2) dosing could be initiated at doses higher than 50 mg. without the need for dose titration. Initiation at higher starting doses would, in turn, be useful by potentially effecting a shorter onset of antidepressive action. Thus, such an improved sertraline dosage form which permitted oral dosing of high doses of sertraline (e.g., 200 mg and higher) with relatively reduced side effects would permit wider therapeutic application of sertraline therapy, and would accordingly provide a significant improvement in dosing compliance and convenience. Likewise, an improved dosage form which lowered the incidence and/or severity of side-effects at lower doses would also be of significant value.
This invention provides an oral, sustained release dosage form of sertraline which decreases, relative to currently marketed instant release sertraline tablet dosage forms which deliver an equivalent bolus dose, the incidence and/or severity of gastrointestinal and/or other side effects such as dizziness, tremor and sweating. The dosage form operates by effecting the release of sertraline at a rate sufficiently slow to ameliorate side effects.
Dosage forms which release more than 70% of their contained sertraline within one hour or less are not xe2x80x9csustained releasexe2x80x9d, and form no part of this invention. This feature thus excludes from the invention immediate release dosage forms containing 40 mg of sertraline or less. Such dosage forms will technically release sertraline at a rate less than 40 mgA/hr, but are excluded because they do not do so in a sustained manner.
In one aspect this invention provides a sustained-release dosage form suitable for administration to a mammal, comprising sertraline, or a pharmaceutically salt thereof, and a pharmaceutically acceptable carrier,
which dosage form releases sertraline into a use environment at a rate not exceeding 0.8 mgA/hr/kg, preferably at a rate not exceeding 0.7 mgA/hr/kg,
provided said dosage form (1) releases not more than 70% of the sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 0.02 mgA/hr/kg. This aspect of the invention describes a dosage form without regard to the size of any particular mammal.
In another aspect this invention provides a sustained-release dosage form suitable for oral administration to a mammal, comprising sertraline, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier,
which dosage form releases sertraline into a use environment at a rate not exceeding 40 mgA/hr,
provided said dosage form (1) releases not more than 70% of the sertraline contained therein within the first hour following entry into said use environment and (2) releases sertraline at a rate of at least 1 mgA/hr. This aspect of the invention describes a dosage form suitable for administration to mammals such as average size adult humans. A dosage form according to the invention thus releases sertraline at a rate of from 1 to 40 mgA/hr. Particular release rate ranges include rates of from 2 to 40 mgA/hr, 3 to 40 mgA/hr, 1 to 30 mgA/hr, 2 to 30 mgA/hr, and 3 to 30 mgA/hr. The ranges 1 to 30 mgA/hr and 2 to 30 mgA/hr are preferred. The ranges 1 to 25 mgA/hr and 2 to 25 mgA/hr are more preferred.
Reference to a dosage form which xe2x80x9creleasesxe2x80x9d sertraline means (1) release of sertraline to a mammal""s gastrointestinal (GI) tract following ingestion or (2) release of sertraline into an in vitro test medium for analysis by an in vitro test as described below. Reference to a xe2x80x9cuse environmentxe2x80x9d can thus be either to in vivo gastrointestinal fluids or to in vitro test medium.
Rates of sertraline release lower than 25, 30 or 40 mgA/hr are also within the scope of the invention and may produce even better side effect profiles, particularly for patients under 50 kg weight for example children. Thus a sertraline release rate of 7 mgA/hr after ingestion represents a release profile within the scope of the invention and may be even more efficacious for ameliorating side effects. The rate must, of course, be high enough to provide therapeutic efficacy, that is, a therapeutically sufficient amount of sertraline should be delivered from the dosage form before the dosage form is excreted with the feces. Accordingly, dosage forms according to the invention should release sertraline at a rate of at least 1 mgA/hr.
The unit xe2x80x9ckgxe2x80x9d as used herein in xe2x80x9cmgA/hr/kgxe2x80x9d refers to kilograms of body weight for the mammal being treated.
It is noted that the mouth-to-anus transit time of a non-disintegrating (e.g., tablet or multiparticulate) dosage form is approximately 24 hours. Dosage forms of this invention release at least 6%, preferably at least 70%, of their contained sertraline within 24 hour. Absorption of sertraline from the lower gastrointestinal (GI) tract, especially from the colon, is less efficient than absorption from the upper GI tract, i.e., from the small intestine, as shown in Example 3. It is accordingly therapeutically advantageous to deliver less sertraline in the lower GI tract and more sertraline in the upper GI tract. Accordingly, controlled release sertraline dosage forms according to the invention release at least 60%, preferably at least 70%, of their contained sertraline within 24 hours, preferably within 18 hours, most preferably within 16 hours.
Although dosage forms as defined above generally release at least 70% of their contained sertraline within 24 hours, a dosage form according to the invention can release substantially all of its sertraline well before 24 hours so long as it otherwise releases sertraline at a rate not exceeding 40 mgA/hr or 0.8 mgA/hr.
The term xe2x80x9cingestionxe2x80x9d as used herein is essentially synonymous with xe2x80x9cswallowingxe2x80x9d.
The invention is particularly useful for administering relatively large amounts of sertraline to a patient. The amount of sertraline contained within the dosage form is preferably at least 10 mgA, and can be as high as 500 mgA or more. The amount contained in the dosage form is more preferably 25 mgA to 400 mgA. The dosage form can be unitary or divided e.g., constituted by two or more units (such as capsules or tablets which, taken together, constitute the dosage form) which are taken at or about the same time.
Sertraline can be employed in the dosage forms of this invention in the form of its pharmaceutically acceptable salts, and also in anhydrous as well as hydrated forms. All such forms can be used within the scope of this invention. The sertraline employed is preferably the free base, hydrochloride, aspartate, acetate, or lactate salts. For convenience and consistency, reference to xe2x80x9csertralinexe2x80x9d in terms of therapeutic amounts or in release rates in the claims is to active sertraline, abbreviated herein as xe2x80x9cmgAxe2x80x9d, i.e., the non-salt, nor-hydrated free base having a molecular weight of 306.2. Amounts in mgA can conveniently be converted to equivalent weights for whatever salt form is desired.
The dosage forms which constitute the subject matter of the invention are, as mentioned, sustained release formulations. The dosage form can be in the form of a tablet, a capsule, a multiparticulate form, a multiparticulate form in a tablet or capsule, or a unit dose packet (sometimes referred to in the art as a xe2x80x9csachetxe2x80x9d). Also included are combination dosage forms, for example those comprising one or more sustained release tablets contained within a capsule shell such as a gelatin capsule shell.
The term xe2x80x9ctabletxe2x80x9d is intended to embrace compressed tablets, coated tablets, matrix tablets, osmotic tablets, and other forms known in the art, and as more fully disclosed and described below,
The term xe2x80x9ccapsulexe2x80x9d is intended to embrace capsules in which the body of the capsule disintegrates after ingestion to release particulate contents which exhibit the desired sustained-release behavior, and also capsules for which the body of the capsule remains substantially intact during its residence in the GI tract.
In a further aspect this invention provides a method for treating a psychiatric or other illness, comprising administering to a mammal in need of such treatment, including a human patient, a therapeutically effective amount of sertraline in a sustained-release oral dosage form which releases the sertraline according to the release rate described above. Such illnesses include those known in the art as being treatable with sertraline, including those mentioned above.
In a further aspect, this invention provides a sustained release dosage form suitable for administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form releases sertraline in vitro at a rate less than 40 mgA/hr, when dissolution tested in a USP-2 apparatus containing a test medium comprising 900 ml of acetate buffer, pH 4.0, which is 0.075 M in NaCl, at 37xc2x0 C., as follows:
(1) if said dosage form is a sustained release tablet or a non-disintegrating sustained release capsule, said USP-2 apparatus is equipped with a paddle stirring at 50 rpm; or
(2) if said dosage form is a multiparticulate, said USP-2 apparatus is equipped with a paddle stirring at 100 rpm;
provided said dosage form (a) releases not more than 70% of the sertraline contained therein within the first hour following initiation of testing and (b) releases sertraline at a rate of at least 1 mgA/hr.
Examples of dosage forms which fall into category (1) above include:
a. sustained release reservoir tablets such as coated diffusive tablets, osmotic tablets, and membrane coated swelling hydrogel tablets;
b. matrix tablets, both disintegrating and non-disintegrating; and
c. non-disintegrating capsules; The capsule shell material should be a non-gelatin polymer such as ethylcellulose or cellulose acetate.
Examples of dosage forms which fall into category (2) above include unit dose packets (also known in the art as xe2x80x9csachetsxe2x80x9d) and powders for oral suspension. Ideally, each particle in a multiparticulate constitutes a self-contained unit of sustained release. The particles can be formed into larger units as by being compressed into a larger tablet-like unit which is more convenient for swallowing. The larger units disintegrate rapidly upon swallowing to give rise to the multiparticulate form, however.
It is noted that the term xe2x80x9cmultiparticulatexe2x80x9d means a plurality of particles wherein each particle is designed to yield controlled release of sertraline. Ideally, each particle in a multiparticulate constitutes a self-contained unit of sustained release. The particles can be formed into larger units. The multiparticulate particles each comprise sertraline and one or more excipients as needed for fabrication and performance. The size of individual particles is generally between about 50 xcexcm and about 3 mm. A multiparticulate predominantly composed of particles toward the low end of this size range is sometimes referred to herein as a powder. Multiparticulates predominantly composed of particles toward the high end of the size range are sometimes referred to herein as beads. Beads having a size outside this range may also be useful.
Any of the dosage forms in (1) or (2) above can be incorporated into a gelatin capsule. If the dosage form is in a gelatin capsule or otherwise gelatin coated, then the dosage form is tested in a USP-2 paddle apparatus as described in (1) or (2), as appropriate depending on the exact dosage form, but with trypsin added to the acetate buffer to a concentration of 0.1 mg/mL. Generally, the amount of or size of the dosage form tested should contain or be equivalent to 200 mgA of sertraline or less. If the dosage form contains more than 200 mgA, then the amount of acetate buffer test medium should be increased proportionately.
The test solution employed above is an acetic acid/acetate buffer solution, pH 4.0, which buffer is 0.075 M in NaCl, and which is intended to simulate gastrointestinal fluids. The test solution is made by making a 0.13M solution of acetic acid in water and then making this solution into an acetic acid/acetate buffer by adding potassium hydroxide, typically as an 0.5M aqueous solution, until a pH of 4.0 has been attained. Sufficient sodium chloride is then added to make the solution 0.075M in NaCl. The temperature of the test solution is maintained at 37 C throughout the dissolution test.
The in vitro release rate is determined by multiplying the incorporated dose by 0.8, and dividing this number by the measured time at which 80% of the incorporated dose has been released and dissolved, as further discussed below. If 80% of the incorporated sertraline is not released in 24 hr, then the mgA sertraline released at 24 hr should be divided by 24 hr, to give the release rate. Further, no more than 40 mgA is released in any one hour. This aspect of the invention thus defines a sustained release dosage form by means of a conveniently performed in vitro test conducted in a standard, well known apparatus. As previously mentioned, not more than 40 mgA should be released in any one hour of the test. It is noted that a USP-2 apparatus, equipped with a paddle, is well known and described in United States Pharmacopoeia XXIII (USP) Dissolution Test Chapter 711, Apparatus 2.
A unitary dosage form is dissolution tested by placing it in a paddle-equipped USP-2 apparatus containing 900 ml of be test solution just described, the test solution having a temperature of 37 deg C, with the paddle stirring at 50 rpm. If the dosage form is a capsule, it is tested in the same manner except that the test solution is augmented to contain 0.1 mg/mL of trypsin. Filtered aliquots (typically 2 or 10 mL) of the dissolution medium are taken at various times, referred to herein as xe2x80x9cpull points.xe2x80x9d The exact time at which an aliquot is removed is not particularly critical, although pull points may be standardized for convenience. The aliquot is filtered and assayed for sertraline content utilizing an HPLC assay or other suitable assay. The data is plotted as mgA sertraline (active sertraline) released (or % sertraline base released) on the y-axis vs time on the x-axis. The time at which 80% of the sertraline dose is released is noted.
To assure accuracy of results, more than one, for example three, or more preferably six, separate dissolution tests should be conducted and the rates determined and averaged.
As mentioned above, an in vitro release rate is calculated from the dissolution test by dividing the quantity of sertraline corresponding to 80% release (determined by multiplying the incorporated dose by 0.8) by the time it takes to effect the 80% release. For example, if a 100 mgA sertraline oral dosage form is tested in this fashion, and 80% of the incorporated sertraline is released in 8 hr, then the release rate is (100 mgxc3x970.8)/18 hr, or 10 mgA/hr. This dosage form is thus within the scope of this invention. As another example, if a 50 mgA sertraline oral dosage form is tested in vitro, and 80% of the incorporated sertraline (as sertraline base) is released in 0.4 hr, then the release rate is (50 mgxc3x970.8)/0.4 hr, or 100 mgA/hr, and the dosage form is not within the scope of the invention.
While there are many methods of describing the in vitro-rate of drug release from a dosage form (e.g. first-order rate constant zero-order rate constant, initial rate, etc.), the method described above provides a clear test which is independent of the mechanism of sertraline release from the dosage form.
It is noted that immediate release sertraline dosage forms are known and commercially available (ZOLOFT(copyright), registered trademark of Pfizer Inc.) as 50 mgA and 100 mgA strength tablets. When 50 mgA ZOLOFT tablets were evaluated using the in vitro dissolution test described above, an average of 80% of the contained sertraline was released (i.e., dissolved in the test fluid) at 0.7 hr after the start of the dissolution test. Thus the immediate release 50 mgA tablet released sertraline at a rate of 57 mgA/hr, calculated by the method described above. When two 100 mgA ZOLOFT tablets (total dose 200 mgA) were evaluated by the above dissolution test, 80% of the contained sertraline was released at 1.2 hr after starting the test. Thus each 100 mg tablet released sertraline a rate of 67 mg/hr and release for the 200 mg dose was 134 mg/hr, calculated by the method described above. Thus as the above in vitro test illustrates, such dosage forms are outside the scope of this invention.
In a further aspect, this invention provides a sustained release dosage form of sertraline suitable for oral administration to a mammal, which results in a maximum sertraline plasma concentration, Cmax, which is less than 80% of the Cmax determined when an equal dose of sertraline is orally administered in the form of an immediate release bolus (such as an immediate-release tablet). This aspect of the invention defines a sustained release dosage form according to the invention by means of an appropriate in vivo test which is conducted in the mammalian species of interest. For example, to test whether a sustained release oral sertraline dosage form ameliorates side effects in humans, the sertraline test dosage form is dosed to half of a group of 12 or more humans and, after an appropriate washout period (e.g. 1 week) the same subjects are dosed with an immediate-release bolus dose at the same strength. The other half of the group is dosed with the immediate-release bolus dose first, followed by the sertraline (sustained-release) test dosage form and the plasma sertraline levels are measured as a function of time. After determining Cmax for each individual on each treatment, an average Cmax is determined. If Cmax for the sustained release sertraline test dosage form is less than 80% of the Cmax for the bolus dose, then the test dosage form will provide a side effect improvement over the bolus dosage form and is within the scope of the invention. In this embodiment, the dosage form may be sustained release, engineered with or without an initial delay period, as disclosed below. It is noted that xe2x80x9cimmediate releasexe2x80x9d means the bolus has not been engineered to include a means for slowing disintegration or dissolution of the dosage form.
Dosage forms which pass either an in vitro test relating thereto as described herein, or an in vivo test relating thereto as described herein (including the Cmax test just described, are within the scope of the invention, as are dosage forms which pass all such tests relating thereto.
As stated above, sustained release sertraline dosage forms provide a decreased Cmax relative to the Cmax for immediate-release dosage forms containing equal amounts of sertraline. That is, sustained-release dosage forms exhibit a Cmax which is less than or equal to 80% of the Cmax provided by an equivalent immediate release dose. Preferred dosage forms additionally provide a total blood drug exposure which again, relative to equivalent immediate-release dosage forms, is not proportionately decreased as much as the sustained release Cmax. A xe2x80x9ctotal blood drug exposurexe2x80x9d is determined as AUC, the area under the curve determined by plotting the concentration of drug in the plasma (Y-axis) vs. time (X-axis). AUC is generally an average value, and would for example be averaged over all the subjects in the crossover study described above. The determination of AUCs is a well known procedure, and is described, for example, in xe2x80x9cPharmacokinetics; Processes and Mathematics,xe2x80x9d by Peter Welling (ACS Monograph 185, Amer. Chem. Soc., Wash. D.C.: 1986). By way of example, suppose a sustained release 100 mgA sertraline dosage form A exhibits a Cmax that is 65% of the Cmax produced by a 100 mgA immediate release sertraline bolus. In a preferred embodiment, sustained release dosage form A will also exhibit an AUC that is higher than 65% of that provided by the bolus.
In a further aspect the invention provides a sertraline sustained release dosage form which exhibits an initial delay in sertraline release when the dosage form enters its environment of use, i.e. after ingestion, followed by sustained sertraline release as described above. During the delay period essentially no sertraline is released, although xe2x80x9cessentially no sertralinexe2x80x9d includes very small release rates less than 1 mgA/hr. This type of dosage form is sometimes referred to herein as a xe2x80x9cdelayed plus sustained releasesxe2x80x9d dosage form. The inventors have demonstrated that certain side effects of sertraline, namely nausea, regurgitation, and diarrhea, are partially or primarily mediated by direct contact of sertraline with the upper gastrointestinal tract, primarily the stomach, rather than mediated systemically, that is via exposure of sertraline to the bloodstream after absorption. Prior to the human clinical studies carried out by the inventors (presented as Example 6 below), the locally mediated nature of these three sertraline side effects was not known. Thus advantageous sertraline dosage forms of this invention include dosage forms which exhibit a spatial or temporal delay in sertraline release after ingestion. Sustained release sertraline dosage forms which exhibit a spatial delay include those which are sensitive to their position along the GI tract, which are independent of time, and which possess a mechanism that largely or completely prevents release of sertraline in the stomach, and which then commence sustained release after the dosage form has passed into the duodenum. Once having commenced sustained release of sertraline, the sustained release is restricted in rate and extent as closed above for xe2x80x9cnon-delayedxe2x80x9d sustained release sertraline dosage forms. Spatially-delayed sustained release dosage forms of this invention commence sustained release of sertraline within approximately 30 minutes, preferably within approximately 15 minutes, of passing out of the stomach into the duodenum.
Temporally-delayed sustained release sertraline dosage forms according to the invention are those which, after ingestion, exhibit a temporal delay before commencing sustained sertraline release. By a temporal delay in this context is meant a delay following ingestion which is not related to the spatial location of the dosage form in the GI tract. Temporally-delayed sustained release sertraline dosage forms exhibit a delay of up to 3 hours after ingestion, preferably up to 2 hours, most preferably up to 1.5 hours. This temporal delay minimizes the exposure of the upper gastrointestinal tract, particularly the stomach, to sertraline after oral ingestion, thus ameliorating locally mediated side effects. After the delay, the dosage form releases sertraline in a manner restricted in rate and extent as disclosed above for xe2x80x9cnon-delayedxe2x80x9d sustained release sertraline dosage forms.
It is noted that in the claims, reference to a xe2x80x9csustained release dosage formxe2x80x9d is to a dosage form not having an initial delay period implemented therein. Reference in the claims to dosage forms having a period of delay implemented therein are specific in pointing this out, for example as to a xe2x80x9csustained release dosage form having an initial delay periodxe2x80x9d, to a temporally or spatially xe2x80x9cdelayed plus sustained release dosage formxe2x80x9d, or similar language such as xe2x80x9csaid dosage form having an initial delay period.xe2x80x9d
It is noted that there is a natural lag period, usually not more than 15 minutes following ingestion, during which time the dosage form is wetted, hydrated, and otherwise affected by bodily (GI) fluids so that it can start to dissolve and release sertraline. This typical lag or induction period of about ten minutes during which wetting occurs is subsumed under the delay period engineered into the dosage form, such that the delay period can also be thought of as about 15 minutes up to 3 hours, preferably about 15 minutes up to 2 hours. If the induction or lag time is not more than 15 minutes, it is not considered to be delayed plus sustained release. Rather, it is simply sustained release.
Thus this invention provides a temporally delayed plus sustained release dosage form suitable for administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
which dosage form, following ingestion by said mammal, releases sertraline into said mammal""s GI tract at a rate less than 1 mgA/hr for an initial delay period of up to three hours, preferably of up to two hours, more preferably of up to 1.5 hr,
and which thereafter releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr, provided said dosage form releases not more than 70% of the sertraline contained therein within the first hour after said delay period.
The dosage form can also be a spatially delayed plus sustained release dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier,
which dosage form, following ingestion by said mammal, releases sertraline into said mammal""s stomach at a rate less than 1 mgA/hr,
and which, after having passed into said mammals duodenum; releases sertraline at a rate-of from 1 mgA/hr to 40 mgA/hr, provided said dosage form releases not more man 70% of the sertraline contained therein within the first hour after passing into said mammal""s duodenum.
The following in vitro tests can be used to determine whether or not a particular dosage form falls within the scope of the invention, depending on whether the onset of the sustained release component is temporally or spatially delayed.
If the dosage form is temporally delayed, the in vitro test can be conducted exactly as previously described for sustained release dosage forms which do not have a temporal delay incorporated therein. The dosage form will release sertraline at a rate less than 1 mgA/hr for a period of up to three hours, or less, corresponding to the length of the delay period, followed by sustained sertraline release at a rate of from 1 mgA/hr to 40 mgA/hr thereafter. Conditions, test apparatus, and test medium can otherwise be the same as for pure sertraline sustained release dosage forms. As with other dosage forms, dosage forms with a temporal delay release not more than 70% of the remaining sertraline contained therein within the first hour following said delay.
If the dosage form is spatially delayed with a pH-trigger, the invention provides a sustained release pH-triggered dosage form suitable for oral administration to a mammal, said dosage form having an initial delay period prior to the onset of sustained release, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when tested in vitro in a USP-2 apparatus,
releases sertraline into 0.1 N HCl at a rate less than1 mgA/hr for at least 1 hour and, thereafter,
releases sertraline into phosphate buffer, pH 6.8 containing 1% polysorbate 80 at a rate of from 1 mgA/hr to 40 mgA/hr, provided the dosage form releases not more than 70% of the remaining sertraline contained therein within the first hour following said delay.
If the dosage form is spatially-delayed with an enzyme-trigger, the invention provides an oral sustained release enzyme-triggered dosage form-suitable for administration to a mammal, said dosage form having an initial delay period prior to the onset of sustained release, comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form, when tested in vitro in a USP apparatus
releases sertraline into 0.1 N HCl at a rate less than 1 mgA/hr for a period of at least 1 hour and, thereafter,
releases sertraline at a rate of from 1 mgA/hr to 40 mgA/hr into phosphate buffer, pH 6.8, containing 1% polysorbate 80 and in the presence of an enzyme suitable for triggering the onset of said sustained release, provided the dosage form releases not more than 70% of the remaining sertraline contained therein within the fist hour following said delay.
In these in vitro tests, 1 mgA/hr is calculated as the average hourly quantity of sertraline released, calculated over the initial 1 hr or longer time period of the test corresponding to the delay period.
It is an object of this invention to decrease the incidence and severity of sertraline-induced side effects. This s particularly important at high doses, for example 100 mg and up, at which the incidence of side effects can be higher. This object is effected, inter alia, by controlling the rate and degree of exposure of the gastrointestinal tract and the systemic circulation to sertraline, in at least a portion of sertraline-dosed patients, thereby reducing the overall incidence and severity of sertraline-induced side effects.
It is noted that sustained-release dosage forms of various types are known and employed conventionally in the art to provide reduced dosing frequency for short half-life compounds and to reduce fluctuations in plasma concentrations, sometimes imparting an improved safety/efficacy profile due to avoidance of multiple plasma drug concentration peaks and troughs throughout the day. Because elimination of sertraline from the human body is characterized by a long half-life of about 23 hours, however, it is surprising that a sustained-release dosage form would offer any benefit.
The present invention further provides a new and useful acetate salt of sertraline, hereinafter referred to as xe2x80x9csertraline acetate,xe2x80x9d pharmaceutical compositions containing sertraline acetate; methods of using sertraline acetate and processes for preparing sertraline acetate.
The present invention further provides a new and useful L-lactate salt of sertraline, hereinafter referred to as xe2x80x9csertraline L-lactate,xe2x80x9d pharmaceutical compositions containing seine L-lactate, methods of using sertraline L-lactate and processes-for preparing sertraline L-lactate.
The present invention further provides a new and useful L-aspartate salt of sertraline, hereinafter referred to as xe2x80x9csertraline L-aspartate,xe2x80x9d pharmaceutical compositions containing sertraline L-aspartate, methods of using sertraline L-aspartate and processes for preparing sertraline L-aspartate.
The instant acetate salt of sertraline is highly water soluble and as such is particularly well-suited for use in a controlled release, for example, sustained release, encapsulated solution or delayed release, dosage form of sertraline. Further, sertraline acetate has advantageous mechanical properties and is chemically and physically stable. These properties permit easy handling of sertraline during formulation of dosage forms and result in tablets which are physically and chemically sable during storage and use.
The instant L-lactate salt of sertraline is highly water soluble and as such is particularly well-suited for use in a controlled release, for example, sustained release, encapsulated solution or delayed release, dosage form of sertraline. Further, sertraline L-lactate has advantageous mechanical properties and is chemically and physically stable. These properties permit easy handing of sertraline during formulation of dosage forms and result in tablets which are physically and chemically stable during storage and use.
The instant L-aspartate salt of sertraline is highly water soluble and as such is particularly well-suited for use in a controlled release, for example, sustained release, encapsulated solution or delayed release, dosage form of sertraline.
Thus the present invention is directed, inter alia, to sertraline acetate.
The present invention is particularly directed to sertraline acetate having the X-ray crystal structure depicted in FIG. 1 and the atomic coordinates recited in Table 40-2.
The present invention is still further directed to sertraline acetatexc2x7xc2xc hydrate.
The present invention is also directed to a method for treating anorexia in a subject suffering from anorexia or the symptoms of anorexia comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating impulse disorders such as trichotillomania, pathological gambling, kleptomania and pyromania in a subject suffering from one of said impulse disorders comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating onychophagia in a subject suffering from onychophagia comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating premenstrual syndrome (also referred to herein as xe2x80x9cpremenstrual dysphoric disorderxe2x80x9d) in a subject suffering from premenstrual syndrome comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating psychotic disorders of the schizophrenic type in a subject suffering from said psychotic disorders or suffering from such symptoms as anxiety, agitation, tension, excessive aggression, social withdrawal or emotional withdrawal comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating inflammatory disorders such as psoriasis and arthritis in a subject suffering from an inflammatory disorder or inflammatory disorders comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating conditions characterized by a hyperactive immune system such as rheumatoid arthritis and lupus in a subject suffering from said conditions comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating mental depression in a mentally-depressed subject comprising administering to said subject an effective amount of sertraline acetate.
The present invention is also directed to methods for treating anxiety-related disorders such as panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, posttraumatic stress disorder, obsessive-compulsive disorder and avoidant personality disorder in a subject suffering from one or more of said anxiety-related disorders comprising administering to said subject an effective amount of sertraline acetate.
The present invention is particularly directed to methods for treating anxiety-related disorders as described in the previous paragraph wherein said anxiety-related disorder is obsessive-compulsive disorder.
The present invention is also directed to methods for treating chemical dependency in a subject suffering from chemical dependency comprising administering to said subject an effective amount of sertraline acetate.
The present invention is further directed to pharmaceutical compositions comprising sertraline acetate and a pharmaceutically acceptable carrier or diluent
The present invention is still further directed to pharmaceutical compositions comprising sertraline acetate having the X-ray crystal structure depicted in FIG. 1 and a pharmaceutically acceptable carrier or diluent.
The present invention is also directed to processes for preparing sertraline acetate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base with acetic acid in the presence of a suitable organic solvent.
The present invention is particularly directed to processes as described in the immediately preceding paragraph wherein said salt of sertraline is sertraline hydrochloride.
The present invention is more particularly directed to processes as described in the immediately preceding paragraph wherein said solvent is hexane.
The present invention is further directed to processes for preparing sertraline acetate comprising reacting sertraline free base with acetic acid in the presence of a suitable organic solvent
The present invention is particularly directed to processes as described in the immediately preceding paragraph wherein said solvent is hexane.
The present invention is also directed to processes for preparing sertraline acetate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base with acetic acid in the presence of a suitable organic solvent and isolating said sertraline acetate from said solvent.
The present invention is also directed to sertraline L-lactate.
The present invention is particularly directed to a form of sertraline L-lactate having the X-ray crystal structure depicted in FIG. 3 and the atomic coordinates recited in Table 48-2.
The present invention is also directed to methods for treating anorexia in a subject suffering from anorexia or the symptoms of anorexia comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating impulse disorders such as trichotillomania, pathological gambling, kleptomania and pyromania in a subject suffering from one of said impulse disorders comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating premenstrual syndrome in a subject suffering from premenstrual syndrome comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating onychophagia in a subject suffering from onycophagia comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating psychotic disorders of the schizophrenic type in a subject suffering from said psychotic disorders or suffering from such symptoms as anxiety, agitation, tension, excessive aggression, social withdrawal or emotional withdrawal comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating inflammatory disorders such as psoriasis and arthritis in a subject suffering from an inflammatory disorder or inflammatory disorders comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating conditions characterized by a hyperactive immune system such as rheumatoid arthritis and lupus in a subject suffering from said conditions comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating mental depression in a mentally-depressed subject comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is also directed to methods for treating anxiety-related disorders such as panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, posttraumatic stress disorder, obsessive-compulsive disorder and avoidant personality disorder in a subject suffering from one or more of said anxiety-related disorders comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is particularly directed to methods for treating anxiety-related disorders as described in the previous paragraph wherein said anxiety-related disorder is obsessive-compulsive disorder.
The present invention is also directed to methods for treating chemical dependency in a subject suffering from chemical dependency comprising administering to said subject an effective amount of sertraline L-lactate.
The present invention is further directed to pharmaceutical compositions comprising sertraline L-lactate and a pharmaceutically acceptable carrier or diluent.
The present invention is still further directed to pharmaceutical compositions comprising sertraline L-lactate having the X-ray crystal structure depicted in FIG. 3 and a pharmaceutically acceptable carrier or diluent
The present intention is also directed to processes for preparing sertraline L-lactate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base with L-lactic acid in the presence of a suitable organic solvent.
The present invention is particularly directed to processes as described in the immediately preceding paragraph wherein said salt of sertraline is sertraline hydrochloride.
The present invention is more particularly directed to processes as described in the immediately preceding paragraph wherein said solvent is ethyl acetate.
The present invention is also particularly directed to processes for preparing sertraline L-lactate comprising reacting sertraline mandelate with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline base into an organic solvent and reacting said sertraline free base with L-lactic acid.
The present invention is more particularly directed to processes as described in the immediately preceding paragraph wherein said solvent is ethyl acetate.
The present invention is further directed to processes for preparing sertraline L-lactate comprising reacting sertraline free base with L-lactic acid in the presence of a suitable organic solvent.
The present invention is particularly directed to processes as described in the immediately-preceding paragraph wherein said solvent is ethyl acetate.
The present invention is also directed to processes for preparing sertraline L-lactate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base with L-lactic acid in the presence of a suitable organic solvent and isolating said sertraline L-lactate from said solvent.
The present invention is also directed to sertraline L-aspartate.
The present invention is also directed to methods for treating anorexia in a subject suffering from anorexia or the symptoms of anorexia comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is also directed to methods for treating impulse disorders such as trichotillomania, pathological gambling, kleptomania and pyromania in a subject suffering from one of said impulse disorders comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is also directed to methods for treating onychophagia in a subject suffering from onychophagia comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is also directed to methods for treating premenstrual syndrome in a subject suffering from premenstrual syndrome comprising administering to said subject an effective amount of sertraline L-aspartate.
The present-invention is also directed to methods for treating psychotic disorders of the schizophrenic type in a subject suffering from said psychotic disorders or suffering from such symptoms as anxiety, agitation, tension, excessive aggression, social withdrawal or emotional withdrawal comprising administering to said subject an effective amount of sertraline La-aspartate.
The present invention is also directed to methods for treating inflammatory disorders such as psoriasis and arthritis in a subject suffering from an inflammatory disorder or inflammatory disorders comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is also directed to methods for treating conditions characterized by a hyperactive immune system such as rheumatoid arthritis and lupus in a subject suffering from said conditions comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is also directed to methods for treating mental depression in a mentally-depressed subject comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is also directed to methods for treating anxiety-related disorders such as panic disorder, generalized anxiety disorder, agoraphobia, simple phobias, social phobia, posttraumatic stress disorder, obsessive-impulsive disorder and avoidant personality disorder in a subject suffering from one or more of said anxiety-related disorders comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is particularly directed to methods for treating anxiety-related disorders as described in the previous paragraph wherein said anxiety-related disorder is obsessive-compulsive disorder.
The present invention is also directed to methods for treating chemical dependency in a subject suffering from chemical dependency comprising administering to said subject an effective amount of sertraline L-aspartate.
The present invention is further directed to pharmaceutical compositions comprising sertraline L-aspartate and a pharmaceutically acceptable carrier or diluent.
The present invention is also directed to processes for preparing sertraline L-aspartate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base wit aspartic acid in the presence of a suitable organic solvent.
The present invention is particularly directed to processes as described in the immediately preceding paragraph wherein said salt of sertraline is sertraline hydrochloride.
The present invention is more particularly directed to processes as described in the immediately preceding paragraph wherein said solvent is hexane.
The present invention is further directed to processes for preparing sertraline L-aspartate comprising reacting sertraline free base with aspartic acid in the presence of a suitable organic solvent.
The present invention is particularly directed to processes as described in the immediately preceding paragraph wherein said solvent is hexane.
The present invention is also directed to processes for preparing sertraline L-aspartate comprising reacting a salt of sertraline with a base in the presence of a suitable organic solvent to form sertraline free base, partitioning said sertraline free base into an organic solvent and reacting said sertraline free base with aspartic acid in the presence of a suitable organic solvent and isolating said sertraline L-aspartate from said solvent.